Potassium-Doped MnO2 Nanoparticles Reprogram Neutrophil Calcium Signaling to Accelerate Healing of Methicillin-Resistant Staphylococcus aureus-Infected Diabetic Wounds

Neutrophils, as first-line immune cells, typically lose their edge within the diabetic wounds accompanied by methicillin-resistant Staphylococcus aureus (MRSA) infections (the D/M setting), playing the role of "more foe than friend" during the healing process. Specifically, reduced influx of calcium ions (Ca2+) and impaired calcium homeostasis yield the dysfunction of neutrophil sequential behaviors in pathogen killing and wound healing, manifesting as suppressed chemotaxis, decreased intracellular reactive oxygen species (ROS) generation, prolonged apoptosis, and retention of neutrophil extracellular traps (NETs). To address this challenge, this study fabricated potassium (K)-doped manganese dioxide nanoparticles (MnO2 NPs), which activated transmembrane Ca2+ channels by inducing neutrophil depolarization via electron transfer. Subsequently, this contributed to the initial Ca2+ influx and reprogrammed Ca2+-dependent behaviors of impaired neutrophils. Also, the potential antimicrobial capacity of K-MnO2 NPs created a favorable extracellular environment that restored calcium homeostasis, enabling apoptotic neutrophils to be removed timely. Therefore, the wounds treated with K-MnO2 NPs in the D/M setting exhibited potent resistance to MRSA and rapid healing, which could be attributed to the synergistic effects of K-MnO2 NPs in leveraging Ca2+ influx and maintaining calcium homeostasis. In brief, K-MnO2 NPs constitute an effective strategy to resist MRSA and rapid wound healing in the D/M setting.